Method of producing serotonin antagonism

ABSTRACT

Certain quinazolinedione derivatives have been found to be effective serotonin antagonists when administered to warm blooded animals either orally or parenterally.

United States Patent [191 Hong Apr. 10, 1973 METHOD OF PRODUCING [56]References Cited SEROTONIN ANTAGONISM UNITED STATES PATENTS [76]Inventor Calzada xochmlw 3,274,194 9/1966 Hayao ..260/256.4

77, Mexlco Primary Examiner-Stanley J. Friedman [22] Flled: 1971Attorney-Joseph C. Schwalbach, Louis E. Davidson, [21] APPL No; 132,912Harry T. Stephenson and George R. Caruso [57] ABSTRACT [52] US. Cl..424/250 Certain quinazolinedione derivatives have been found [51] Int.Cl. ..A6lk 27/00 to be effective serotonin antagonists when ad- [58]Field of Search ..424/250, 251 mini red -warm l o ed nimals i her or llyr parenterally.

10 Claims, No Drawings METHOD OF PRODUCING SEROTONIN ANTAGONISMBACKGROUND OF THE INVENTION Various pharmacological agents such as1-methyl-4- 5 -dibenzocycloheptatrienylidene )-piperidine hydrochloride.(hereinafter referred to as cyproheptadine) and N-[ l-(hydroxymethyl)-propyl]- 1 -mehtyl lysergamide (hereinafter referred to asmethysergide) which antagonize the action of serotonin have been used inthe past to treat migraine headaches and to SUMMARY OF THE INVENITON Ithas now been discovered that serotonin antag onism can be produced in awarm blooded animal by admisinstering an effective amount of a compoundof the formula in which R is hydrogen or acetamido and Y is hydrogen orchlorine, and non-toxic, pharmacologically acceptable acid additionsalts thereof, Extremely effective are the maleates and hydrochloridesof the compounds wherein Ris acetamido or hydrogen and Y is hydrogen inthe above formula. These compounds are fully described in U.S. Pat. no.3,274,194 owned by the as signee of the present invention.

The quinazolinedione derivatives employed in the method of thisinvention can be administered orally or parenterally in combination witha non-toxic pharmaceutical, liquid or solid carrier. In one dosage formthe active ingredient, preferably as a hydrochloride or maleate, isdissolved in sterile, aqueous, isotonic saline solution and stored invials contining from l to 5 milligram dosages. This solution is injectedintravenously or intramuscularly, a therapeutic dose ranging from r tomilligrams per day of said ingredient for animals requiring a serotoninantagonist to gain weight.

To prepare other compositions suitable for use as serotonin antagonistsone of the compounds encompassed within the formula hereinbefore setforth is mixed with liquid carriers such as water, vegetable oils,benzyl alcohol, propylene glycol and the like to form a solution,suspension or emulsion. If desired, other substances such as preservingagents, stabilizing agents, wetting or emulsifying agents, buffers orsalts can be added. The compounds can also forrriulated with solidcarriers such as milk sugar, acacia, corn starch, talc, stearic acid,lactose or magnesium stearate and compressed into tablets containingfrom 2 to 20 milligrams of active ingredient for oral administration ata dosage of from 4 to 60 milligrams per day. Such tablets can be entericcoated with shellac or cellulose acetate phthalate in a manner well kownto those skilled in tablet making art. Likewise, the quinazolinedionecompounds per se or in combination with any of the liquid or solidcarriers previously enumerated can be sealed in a gelatin capsule toform an oral dosage unit containing from 2 to 20 milligrams of one ofsaid compounds.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 The ability ofseveral quinazolinedione compounds to block the actions of serotonin wascompared with cyproheptadine and methysergide as the referenceantiserotonin agents by four different methods set forth below:

1. Rat uterine segment. In this method uterine segments from ratspretreated with diethylstilbestrol 18 hours previously were placed'inchambers filled with de Jalon solution at 30C. Uterine contractionsinduced by a test concentration of 0.05 micrograms per milliliter ofserotonin were obtained before and after the contact of preparationswith the compounds tested.

2. Guinea Pig Lung Resistance to Inflation. The procedure described byKonzett et al. in Arch. Exptl. Path. PharmakoL, 195, 71 (I940) wasemployed in which guinea pigs were anesthetized, artificial respirationwas installed and a collateral from the respiration pump was passedthrough a 10 centimeter water resistance. The volume of the pump wasadjusted so that under control conditions the air delivered per strokedid not pass the water resistance, whereas the intravenous injection of2 micrograms per kilogram of serotonin caused the air to overflow. Inthis manner, the blockade of serotonin responses produced b the previousadministration of the test compounds was determined. I 3. Blood PressureOf The Ganglion Blocked Dog. Pressor responses to intravenous injectionsof 25 micrograms per kilogram 'of serotonin were recorded fromanesthetized dogs under ganglionic blockade induced by chlorisondamineknown chemically as N-[(2-dimethylammonium)ethyl]- 4,5,6,7-tetrachloroisoindolinium dimethochloride. The antagonism ofserotonin responses produced by the administration of the test compoundswas then assessed. Rat Paw Edema. In this test male rats were orallygiven the test compounds one hour before the subplantar injection of 5micrograms of serotonin. Paw volumes were determined by mercurydisplacement as described by Winter et al. in Proc. Soc. Exp. Biol. Med.1 1 1, 544 I962) immediately and 30 minutes after the serotonininjection. Inhibition of the edema induced by the test compounds wasassessed in relation to the edema found in the control rats.

The toxicity of cyproheptadine and Compounds A, B and D of Example 1 wasdetermined by administration of these compounds in graduated oral dosesto mice with the following results, LD being the lethal dose for 50percent of the mice treated:

Tcst Compound LD in mgJkg.

A 1000 B 740 D 1000 Cyprohcptadinc I65 It is apparent from the foregoingexamples that the quinazolinedione compounds employed in the presentinvention are very effective serotonin antagonists and are far lesstoxic than the known agents presently used for this purpose. Similarresults are obtained when other compounds included in the generalformula set forth in the summary of this invention are employed tocounteract serotonin responses.

What is claimed is:

1. A method of producing serotonin antagonism which comprisesadministering to warm blooded animals, having pathologic disorderswherein serotonin is implicated, an effective amount of a materialselected from the group consisting of a compound of the formula whereinR is selected from the group consisting of hydrogen or acetamide and Yis selected from the group consisting of hydrogen or chlorine, andnon-toxic, acid addition salts thereof.

2. A method as in claim 1 in which the compound is administered orally.

3. A method as in claim 1 in which the compound is administeredparenterally.

4. A method as in claim 2 in which from 4 to mg. per day of the compoundis employed.

5. A method as in claim 3 in which from 0.5 to 15 mg. per day of thecompound is employed. I

6. A method as in claim 1 in which the compound employed is ahydrochloride.

7. A method as in claim 1 in which the compound employed is a maleate.

8. A method as in claim 1 in which the compound employed is6-acetamido3-[ 3-( 4-phenyl- 1 piperazyl )propyl l ,2,3,4-tetrahydroquinazoline-2,4- dione maleate.

9. A method as in claim 1 in which the compound employed is 3-[ 3-(4-phenyll -piperazyl )propyl l ,2,3,4-tetrahydroquinazoline-2,4-dionehydrochloride.

10. A method as in claim 1 in which the compound employed is 3- 3-(4-p-chlorophenyll piperazyl)propyl]- l ,2,3,4-tetrahydroquinazoline-2,4-dione maleate.

2. A method as in claim 1 in which the compound is administered orally.3. A method as in claim 1 in which the compound is administeredparenterally.
 4. A method as in claim 2 in which from 4 to 60 mg. perday of the compound is employed.
 5. A method as in claim 3 in which from0.5 to 15 mg. per day of the compound is employed.
 6. A method as inclaim 1 in which the compound employed is a hydrochloride.
 7. A methodas in claim 1 in which the compound employed is a maleate.
 8. A methodas in claim 1 in which the compound employed is6-acetamido-3-(3-(4-phenyl-1-piperazyl)propyl)-1,2,3,4-tetrahydroquinazoline-2,4-dionemaleate.
 9. A method as in claim 1 in which the compound employed is3-(3-(4-phenyl-1-piperazyl)propyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione hydrochloride.
 10. A method as in claim 1 in which the compoundemployed is3-(3-(4-p-chlorophenyl-1-piperazyl)propyl)-1,2,3,4-tetrahydroquinazoline-2,4-dionemaleate.